tbuckley/cabot-search huggingface dataset:
Comparison of generic and specific anxiety in patients treated with apalutamide plus active surveillance vs active surveillance alone for low and intermediate risk prostate cancer.
Authors: Gwenaelle Gravis, Rajae Touzani, Jochen Walz, Guillaume Ploussard, Pierre-Henri Savoie, Matthieu Durand, Gregoire Poinas, Jean-Baptiste Beauval, Romain Mathieu, Youness Ahallal, Sebastien Vincendeau, Mathilde Guerin, Laurys Boudin, Sebastien Crouzet, Naji Salem, Cecile Vicier, Pauline Heux, Patrick Sfumato, Geraldine Pignot, Patricia Marino
Journal: Journal of Clinical Oncology (2023)

e17093 Background: Active surveillance (AS) is a standard of care for low-risk prostate cancer (PCa). However, it is not yet clear whether AS may be a source of anxiety in patients (pts) compared to pts receiving treatment. The objective of this study is to compare anxiety in pts receiving apalutamide monotherapy plus AS versus AS alone in pts with low and intermediate-risk PCa. Methods: The study was conducted, in pts enrolled in a multicenter randomized phase 2 trial comparing AS with apalutamide (240 mg) 6 months versus AS alone. Participants completed questionnaires at baseline, 3, 6, and 12 months after diagnosis. We assessed anxiety and depression using the Hospital Anxiety and Depression Scale (HADS) and prostate-specific anxiety using the Memorial Anxiety Scale for Prostate Cancer (MAX-PC). Results: Patients were randomized to AS alone (n = 40) or AS + apalutamide (n = 51). Anxiety questionnaire, response rates, were 98%, 88%, 92%, and 82%, respectively, at baseline, 3 months, 6 months, and 12 months. HADS scores were similar between treatment groups (p &gt; 0.05 at each assessment point) and did not change significantly over time (p &gt; 0.05 for each comparison over time). By analyzing the general MAX-PC anxiety score, we observed that for pts on treatment, anxiety decreased significantly at 3 months compared to baseline (p = 0.01), then remained stable between 3 and 6 months. For pts on AS, anxiety remained stable during the first 3 months and decreased significantly after 3 months (p = 0.018). At the end of treatment (6 months), anxiety increased significantly in pts in the apalutamide arm (p = 0.05) while it remained stable for pts on AS alone. One year after inclusion, the MAX-PC general anxiety levels returned to baseline for both groups of pts. However, for the prostate cancer anxiety subscale, scores decreased significantly from baseline to 12 months in the AS alone group (p = 0.031). Conclusions: Anxiety was reduced in the apalutamide arm after the start of treatment, but this effect was transient and disappeared at the end of treatment. The decrease in anxiety appears to be delayed over time for AS patients, but after a few months, these patients experience a decrease in anxiety levels, suggesting that patients have become accustomed to not being treated. Better detection of PCa specific anxiety was observed, with disease-specific tools such as MAX-PC compared with generic anxiety detection with HADS. Clinical trial information: NCT03088124 .
Trends in the use of maintenance therapy in ovarian cancer.
Authors: Naomi N. Adjei, Allen Haas, Hui Zhao, Kristin Marianne Primm, Charlotte C. Sun, Larissa Alejandra Meyer
Journal: Journal of Clinical Oncology (2023)

6585 Background: Emerging maintenance therapies in advanced ovarian cancer (OC) remain of high interest since 70% of patients (pts) will relapse and ultimately succumb to OC. This study analyzes nonclinical factors associated with maintenance therapy (MT) in OC. We define MT in OC as the use of polyADP-ribose polymerase inhibitors (PARPi) and/or bevacizumab (bev) following platinum-based chemotherapy. Methods: We used data from Optum’s de-identified Clinformatics Data Mart Database F to conduct an analysis of OC pts with Medicare or commercial health insurance. Pts were included if they had 1 inpatient or 2 outpatient diagnosis codes for OC from 01/2017 to 12/2020 and received platinum-based chemotherapy after diagnosis. Pts were excluded if they did not have continuous coverage from diagnosis until 6 months after completion of platinum-based chemotherapy or death. MT was identified by insurance claims for PARPi or bev received within 6 months after completion of platinum-based chemotherapy. Descriptive statistics were used to summarize patient characteristics. Multivariable logistic regression was used to evaluate associations between pts’ nonclinical characteristics and MT use. Trends in MT use were reviewed by year. Subgroup analysis comparing trends in PARPi use to bev use was also performed. The median time from last chemotherapy until initiation of MT was 22 days. Results: 5,652 pts were included in the study with a median age of 70 years. The majority were white (70.7%), Medicare-insured (71.8%), and treated in the South (42.8%). 33.6% of pts received MT and 66.4% of pts received neither PARPi nor bev. More pts received bev alone (19.6%) compared to PARPi alone (10.3%) or combination MT (3.7%). Olaparib was the most commonly prescribed PARPi. After adjusting for insurance type, both PARPi and bev use increased significantly over time from 2017 to 2021. Pts with more comorbidity burdens (i.e. higher Elixhauser comorbidity index) were more likely to receive MT compared to pts with less comorbidity [OR (95% CI): 1.44 (1.26-1.65)]. MT use was significantly associated with treatment in the South compared to the Northeast [1.22(1.01-1.46)] and younger age, pts &gt; 76 years were less likely to use MT compared to pts &lt; 56 years old [0.78 (0.62-0.98)]. In the subgroup analysis, PARPi use was significantly associated with age, race and region compared with no MT use, while bev use was not associated with these factors. Conclusions: Age, comorbidity status, and geographic location of treatment were associated with MT use. The increasing use of MT over time is consistent with published data since both agents have demonstrated a progression free survival advantage and have tolerable toxicity profiles. With increasing focus on MT in OC, a better understanding of nonclinical factors associated with MT use is imperative to eliminating potential disparities in OC outcomes.
MELK and Del-1 as druggable targets in TNBC.
Authors: In Hee Lee, Soo Jung Lee, Byeongju Kang, Jeeyeon Lee, Ho Yong Park, Ji-young Park, Jee-Young Nora Park, Yee Soo Chae
Journal: Journal of Clinical Oncology (2023)

e15100 Background: In our previous study, the researchers found that Del-1 was a promising predictive marker for breast cancer. However, the Del-1 downstream targets and biological effectors remain unknown and undruggable in breast cancer. We used RNA-seq to analyze the transcriptome and investigate the mechanism of Del-1 in regulating the course of breast cancer to uncover a druggable target. Methods: To evaluate the expression levels of Del-1 and MELK, mRNA levels in several breast cancer cell lines were analyzed. Due to the heterogeneity of TNBC, eight different TNBC cell lines were analyzed (BT20, TNBC; MDA-MB-468, basal-like 1; HCC-1806, basal-like 2; DU4475, Immunomodulatory; BT549, mesenchymal-like; MDA-MB-231, mesenchymal stem-like; HS578T, mesenchymal stem-like; MDA-MB-453, TNBC Luminal androgen receptor). Total RNA was isolated using RNAiso Plus (TaKaRa, Otsu, Shiga, Japan). Libraries were prepared from total RNA using the NEBNext Ultra II Directional RNA-Seq Kit. High-throughput sequencing was performed as paired-end 100 sequencing using NovaSeq 6000 (Illumina, Inc., USA). OTS167 was treated for inhibition of MELK. The effects of MELK on cell proliferation and invasion were determined using MTT and Matrigel Transwell assays. To further investigate the relationship between DEL-1 and MELK, the researchers performed dual inhibition of DEL-1 &amp; MELK. Results: Del-1 and MELK expression were significantly increased in TNBC cell lines compared to luminal or HER 2 positive breast cancer cell lines. Expression of Del-1 and MELK was dramatically enhanced in MB 468, HCC-1806, and MB 231 TNBC cell lines. Three TNBC cell lines were transfected with Del-1-specific siRNA to examine the effect of Del-1 downregulation on breast cancer. Del-1 knockdown HCC-1806 &amp; MDA-MB 231 cells significantly decreased MELK expression, suggesting the possible relation between Del-1 and MELK. OTS 167, a MELK inhibitor, significantly inhibits breast cell proliferation and promotes cell apoptosis (MBA-MB-468, p &lt; 0.001). Furthermore, when the OTS 167 was treated, the cell viability decreased as the dose of the MELK inhibitor increased, and the degree was the greatest in MBA-MB 468, basal-like 1 TNBC cell line. To further investigate the relationship between DEL-1 and MELK, the researchers inhibited DEL-1 and then MELK in MTT assay. Dual inhibition significantly reduced cell viability in MDA-MB468 and MDA-MB 231 cell lines, with the basal-like 1 cell lines showing the most significant effect. Conclusions: In this study, we sought to investigate the association between De1-1 and MELK in TNBC cell lines and tumor tissue. We found that MELK is downstream of del-1 and is a promising target, especially in the basal-like 1 subtype. Further research is warranted.
Circulating tumor DNA in decision-making of patients with metastatic colorectal cancer after failure of first-line treatment containing cetuximab: A single-center, phase II trial.
Authors: Jianling Zou, Wentao Yang, Wenhua Li, Jieyun Zhang, Qirong Geng, Jinjia Chang, Chenchen Wang, Xin Hu, Zhiyu Chen
Journal: Journal of Clinical Oncology (2023)

e15584 Background: Genetic status is constantly changing after receiving cetuximab. To analyze the molecular characteristics in mCRC after first-line treatment containing cetuximab and adjust second-line targeted therapy strategies, we conducted this prospective study. Methods: Patients with measurable mCRC were enrolled. Main eligibility criteria included initial RAS and BRAF wild-type genetic status on tumor tissue; prior first-line regimens including cetuximab, and then showed progression disease. The ctDNA status was detected: bevacizumab would be applied if there was RAS mutation; the combination of vemurafenib, cetuximab and irinotecan would be used if there was BRAF mutation; trastuzumab would be used if there was HER2 amplification; cetuximab or bevacizumab would be applied according to investigators discretion if no related secondary variation. The primary endpoint was ORR; secondary endpoints were DCR, PFS, OS, safety and tolerability. Results: Twenty-two patients were enrolled from Apr 8, 2021 to Nov 18, 2022. Fifty percent (11/22) were males and the median age was 56.5 years. 59.1% (13/22) patients received bevacizumab, 36.4% (8/22) patients received cetuximab, and 4.5% (1/22) patients received trastuzumab and pyrotinib. 52 variations were detected in 22 patients before second-line therapy, with a positive rate of 95.5%. TP53 (90.9%, 20/22) was the most mutated gene, followed by APC (86.4%, 19/22). The percentage of secondary KRAS mutation was 9.1% (2/22), BRAF mutation was 0, ERBB2 amplification was 4.5% (1/22), and ERBB2 mutation was 9.1% (2/22). For 8 patients with serial ctDNA detection, the number of gene variation was decreased during disease remission (10 vs. 23) and increased again during progression (23 vs. 10). The ORR was 40.9% (9/22) for all patients. And it was 38.5% (5/13) and 37.5 % (3/8) separately for patients received bevacizumab or cetuximab (p = n.s.). The DCR was 86.4% (19/22) for all patients. And it was 92.3% (12/13), and 75% (6/8) for patients received bevacizumab or cetuximab separately (p = 0.013). The median PFS was 8.6 months in all patients. And it was 11.6 months and 4.6 months separately in patients received bevacizumab or cetuximab (p = 0.013). The median OS was 12.4 months in all patients. And it was 14.5 months and 11 months separately in patients received bevacizumab or cetuximab (P = 0.27). In addition, no difference in treatment related serious adverse advents grade 3-5 was observed. Conclusions: Circulating Tumor DNA is a promising biomarker for assessing treatment efficiency and guiding second-line treatment decisions in patients with mCRC. The bevacizumab-based second line treatment increases DCR and PFS than continuously cetuximab-based treatment, and had a better tendency in OS. Clinical trial information: NCT04831528 .
A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART SWOG 1609) in patients with refractory gallbladder cancer (cohort 48).
Authors: Sandip Pravin Patel, Elizabeth Guadarrama, Young Kwang Chae, Chih-Yi Liao, Anup Kasi, Grace R. Tarabay, Thomas J. George, Liam Chung, Gabby Lopez, Christine McLeod, Megan Othus, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles David Blanke, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2023)

e16330 Background: Immune checkpoint blockade has improved outcomes in multiple tumor types, however little is known about the efficacy of these agents in rare tumors. We report the results of the gallbladder cohort of SWOG S1609 Dual Anti–CTLA-4 and anti–PD-1 blockade in Rare Tumors (DART). Methods: We performed a prospective, open label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the gallbladder cohort reported here. Eligible patients had progressed following at least one line of standard systemic therapy, and did not have an approved or standard therapy available that had been shown to prolong survival. All participants received nivolumab 240 mg i.v. every 2 weeks and ipilimumab 1 mg/kg i.v. every 6 weeks on a continuous schedule. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease &gt;6 months, and toxicity Results: Nineteen patients (79% female) with a median age of 60 years were enrolled and received treatment. The median prior lines of therapy was 2 (range 1-6). The confirmed overall response rate was 16% [complete response, n=1 (5%); partial response, n=2 (11%)] (duration = 35+, 16, 13 mo). The unconfirmed overall response rate and clinical benefit rate were both 32% [complete response, n=1 (5%); partial response, n=5 (26%); stable disease &gt; 6 months, n=0 (0%)]. The 6-month progression-free survival was 26% (95% CI 12-55%); median overall survival was 7.0 months (95% CI, 3.9-19.1 months). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was one death from hepatic failure possibly related to treatment in the setting of progressive liver metastasis and biliary infection. Conclusions: Ipilimumab plus nivolumab demonstrated a 16% ORR in patients with gallbladder cancer including a complete response lasting 35+ months; The unconfirmed overall response rate was 32%. Clinical trial information: NCT02834013 . [Table: see text]
FLOT plus nivolumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: Results from the randomized phase 2 IKF-S628/AIO-STO-0417 (Moonlight) trial of the AIO.
Authors: Sylvie Lorenzen, Thorsten Oliver Goetze, Ralf Dieter Hofheinz, Peter C. Thuss-Patience, Tobias Nicolaas Dechow, Jorge Riera-Knorrenschild, Gunter Schuch, Kim Barbara Luley, Christine Koch, Eray Goekkurt, Harald Schmalenberg, Thomas Jens Ettrich, Udo Lindig, Daniel Pink, Michael Bitzer, Claus Bolling, Nils Homann, Sabine Junge, Claudia Pauligk, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2023)

4045 Background: FOLFOX plus nivolumab (nivo) has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas. FLOT is a well-established standard of care triplet regime. Some physicians may consider a triplet in patients with aggressive disease. The aim of this Arm C part of the Moonlight trial was to evaluate the safety and efficacy of the combination of FLOT plus nivo. Methods: Moonlight is a multi-cohort phase-II trial. The results for Arm C evaluating FLOT + nivo (240 mg) q2w as first-line therapy in all-comers are presented here. Primary endpoint was progression-free survival at 6 months (PFS@6), main secondary endpoints were safety, OS, and overall response rate (ORR). Results: Fifty-two patients were enrolled. Baseline characteristics were: median age 61y, GEJ 65%. Sixty-five percent had centrally assessed PD-L1 CPS≥1 (available in 96% of pts). Pts. received a median number of 8 cycles of FLOT and nivo and 42% received further line treatment. FLOT plus nivo was well tolerated and feasible with the most frequent adverse events of ≥ grade 3 being decreased neutrophils (40.4%), anemia (5.8%) and thromboembolic events (7.7%). After a median follow-up of 9.4 months, 3- and 6-month progression-free survival rates were 85% and 42%, respectively. Median PFS was 6.6 months and median OS 10.8 months. ORR and disease control rate (DCR) were 54% and 87%, respectively. Compared to the pooled study cohorts A and A1 (n = 90 pts) utilizing mFOLFOX plus nivo and ipilimumab (non-randomized comparison), FLOT plus nivo was associated with greater DCR (87% vs. 78%) and 3-months PFS (85% vs. 72%). Conclusions: FLOT and nivo is feasible and seems to be associated with improved disease control in the early course of therapy. FLOT plus nivo may represent an option for select patients with aggressive, rapidly progressive disease. Clinical trial information: NCT03647969 .
Efficacy of bi-weekly docetaxel in hormone-sensitive metastatic prostate cancer (mHSPC).
Authors: Milton Alberto Lombana Quinonez, Ana Milena Torres, Guido Gonzalez
Journal: Journal of Clinical Oncology (2023)

e17070 Background: In pts with mHSPC, docetaxel in a three-week schedule is associated with better overall survival (OS) vs androgen suppression alone, principally in pts with high tumor volume(HV). In pts with mCRPC stage, biweekly docetaxel demonstrated greater efficacy and a better toxicity profile. There are few published data about the use of bi-weekly docetaxel in pts with mHSPC. Methods: Pts with mHSPC and treated with bi-weekly docetaxel from January 2014 to December 2020 at The Comprehensive Cancer Center Clinica de Occidente in Cali-Colombia, were retrospectively identified. We collected relevant variables from electronic medical records. Our primary objective was to determine the efficacy in OS and the incidence of febrile neutropenia (FN). We performed Kaplan Meier, and cox regression analysis with relevant variables. Results: 69 pts were included, with a mean follow-up time of 45 months. Median age was 72y, 82% had ECOG PS 0/1, 74% grade group 4-5, 23% visceral metastases, and 93% de novo metastatic disease. The median OS was 51 months, and 39% at 5 years. In HV and de novo metastatic pts, the median OS was 49 months. The median time to development of mCRPC was 34 months. 35% of the patients had a PSA &lt; 0.2ng/mL at month 6. In the univariate analysis, pts with HV (HR 10.49 95% CI 1.43-76.50, P = 0.0005), PSA &gt; 0.2ng/mL (HR 4.43 95% CI 2.09-9.41, P = 0.0000), imagen objective response rate (ORR) (HR 1.47 95% CI 1.09-1.95, P = 0.0156) and PS ECOG &gt; 0, (HR 3.3 CI95% 1.31-8.45, P = 0.003) had worse OS. Neither histologic grade 5 (HR 1.07, P = 0.8), visceral metastases (HR 1.2, P = 0.57), or de novo metastatic disease (HR 0.84, P = 0.74) were significantly associated. In the multivariate analysis, only PSA of &gt; 0.2ng/mL at 6 months remained significantly [Table 1]. FN was detected in 3.2% of patients. Conclusions: We report the study with the largest number of patients and follow-up time (median 42.5 months) in patients with mCSPC who used biweekly docetaxel in addition to standard androgen suppression. The outcomes are similar, indirectly compared, to those reported in the CHAARTED study in OS, specifically in the de novo high-volume metastatic subgroup (CHAARTED 48 months, current study 49 months), better time to CRPC (20 months CHAARTED, 34 months current study), and with a lower incidence of FN (6% CHAARTED, 2% current study). None of the pts used primary granulocyte colony-stimulating factor prophylaxis. The use of biweekly docetaxel in this scenario offers high efficacy with less toxicity. Randomized studies are strongly recommended to confirm these results. [Table: see text]
EphrinB2 (B2) expression predicts poor response to PD1/L1 antibodies (Ab) in metastatic urothelial carcinoma (mUC).
Authors: Sarmad Sadeghi, Imran Siddiqi, Karam Ashouri, Denice D. Tsao-Wei, Jon P Cogan, Alexandra Jackovich, Krithika Chennapan, Dory Freeman, Jillian O'Toole, Adrie van Bokhoven, Kathleen Torkko, Inderbir Gill, Parkash S. Gill, Thomas W. Flaig, Guru P. Sonpavde
Journal: Journal of Clinical Oncology (2023)

4575 Background: B2 is a ligand for EphB4 which enhances tumor invasion, proliferation, survival and promotes angiogenesis. A prior analysis of TCGA data from 409 muscle invasive bladder cancer (MIBC) patients (pts) demonstrated that high (34%) B2 gene expression had poor survival vs. low (66%) expression (Hazard Ratio 0.7 p = 0.02). Our phase II trial of sEphB4-HSA (JCO PMID 35984996) which targets B2, in combination with pembrolizumab in previously treated mUC (N=70) demonstrated an objective response rate (ORR) of 37%. Among pts with high expression of B2, ORR was 52% with 24% complete response (CR). This retrospective study examined the ORR to PD1/L1 Ab in pts with mUC and its correlation with B2 mRNA expression. Methods: Pts with mUC who had received anti PD1/L1 Ab were eligible if they had radiographic response data and tumor tissue for B2 testing. Pts’ demographics and disease characteristics were abstracted. Radiographic images were reviewed using RECIST 1.1. Tumor specimens were analyzed for intensity of B2 expression using in-situ hybridization (ISH). Scores of 2-4 were considered High (Hi) and 0-1 were considered Low (Lo) expression. Standard descriptive statistics were used to summarize study results. Fisher’s exact test was used to test the association of ORR with B2 expression using SAS 9.4. Results: 120 (N) pts from University of Southern California (USC, n=49), Dana Farber (DFCI, n=55), and University of Colorado (UC, n=16) met were included. 88 pts were male (73%). Median age was 72. PD1/L1 Ab were administered in the post-platinum progressive disease (n=95, 79%) and first-line setting (n=25, 21%) and included pembrolizumab (n=88, 73%), atezolizumab (n=26, 22%) and nivolumab, avelumab, and durvalumab, 3%, 1%, and 1%, respectively. Objective response rate (ORR) defined as radiographic CR plus partial response (PR) were calculated and summarized. Among all pts (N=120), ORR was 20% (95% CI 13-28). 62% had B2 Hi expression with a response rate of 12%, and 38% had B2 Lo expression with a response rate of 33%, p=0.009). These proportions were similar for each institution. Conclusions: In addition to conferring poor prognosis in MIBC, B2 expression is associated with poor ORR to PD1/L1 Ab monotherapy in mUC. Given that the combination of B2 inhibition &amp; pembrolizumab was more active in B2 expressing mUC, these data provide further rationale for investigating B2 as a mechanism of resistance to PD1/L1 ab, biomarker of response and a therapeutic target. [Table: see text]